Dendritic spines are highly specialized postsynaptic structures which receive the vast majority of excitatory input. Changes in their morphology and density have been associated with learning as well as long-term potentiation of synaptic efficacy which is thought to represent the cellular correlate of learning and memory. Aging in humans, nonhuman primates and rodents is usually accompanied by memory deficits, loss of dendritic spines, and in rodents, age-related memory deficits have been correlated with LTP deficits. Such changes in spine function during aging do not arise from significant cell loss, which is normally minimal during aging, but rather may indicate specific alterations in the mechanisms which underlie spine formation and maintenance. Elucidating fundamental mechanisms contributing to spine induction and maintenance becomes critical not only for understanding the basis for spine-related deficits in aging, but also for designing rational therapies aimed at preserving spine function. Estrogen treatment stimulates production of dendritic spines in rat hippocampus, and a growing body of data shows strong links between estrogen replacement therapy in postmenopausal women and a decreased risk of dementia. Estrogen induction of dendritic spines requires NMDAR activation, and binding studies suggest that changes in NMDAR subunit combination may be involved. The signaling pathway also appears to include activation of a serine-threonine protein kinase. One such kinase, type II calcium-calmodulin-dependent protein kinase (CaMKII) is a likely candidate in that it is concentrated within dendritic spines and its activation is required for the induction long-term potentiation . Thus, changes in NMDAR subunit synthesis, association or localization and activation of CaMKII are likely to participate in dendritic spine induction and will be investigated as part of a long term goal to elucidate the mechanisms of estrogen-mediated dendritic spine regulation.